Emerging oral therapeutic strategies for inhibiting PCSK9 DOI Creative Commons
Nicola Ferri, Giorgia Marodin

Atherosclerosis Plus, Journal Year: 2024, Volume and Issue: 59, P. 25 - 31

Published: Dec. 12, 2024

Pharmacological inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) have been firmly established to be an effective approach reduce low-density lipoprotein (LDL) cholesterol levels and cardiovascular events. Subcutaneous administration monoclonal antibodies (evolocumab alirocumab) every 2 or 4 weeks determined a 60 % reduction LDL levels, while the GalNac-siRNA anti PCSK9 (inclisiran) provided lipid lowering activity (-50 %) after initial subcutaneous dose, repeated 3 months followed by maintenance dose 6 months. Although these two approaches potentiality bring majority patients at high very-high risk appropriate targets, their cost represent strong limitation for large-scale use. These problems could overcome development small chemical molecules as oral therapy controlling hypercholesterolemia. In present review, we summarized pharmacological properties that are currently under clinical (DC371739, CVI-LM001, AZD0780), including mimetic peptides enlicitide decanoate (MK-0616) NNC0385-0434.

Language: Английский

Hypercholesterolemia and inflammation—Cooperative cardiovascular risk factors DOI Creative Commons

Antonio Gallo,

Wilfried Le Goff,

Raul D. Santos

et al.

European Journal of Clinical Investigation, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 6, 2024

Abstract Background Maintaining low concentrations of plasma low‐density lipoprotein cholesterol (LDLc) over time decreases the number LDL particles trapped within artery wall, slows progression atherosclerosis and delays age at which mature atherosclerotic plaques develop. This substantially reduces lifetime risk cardiovascular disease (ASCVD) events. In this context, plaque development vulnerability result not only from lipid accumulation but also inflammation. Results Changes in composition immune cells, including macrophages, dendritic T B mast cells neutrophils, along with altered cytokine chemokine release, disrupt equilibrium between inflammation anti‐inflammatory mechanisms sites. Considering that it is a competition LDLc inflammation, instead they are partners crime, present narrative review aims to give an overview main inflammatory molecular pathways linked raised describe impact lipid‐lowering approaches on burden. Although remarkable changes driven by most recent lowering combinations, relative reduction C‐reactive protein appears be independent magnitude lowering. Conclusion Identifying clinical biomarkers (e.g. interleukin‐6) possible targets for therapy holds promise monitoring reducing ASCVD burden suitable patients.

Language: Английский

Citations

7
Emerging oral therapeutic strategies for inhibiting PCSK9 DOI Creative Commons
Nicola Ferri, Giorgia Marodin

Atherosclerosis Plus, Journal Year: 2024, Volume and Issue: 59, P. 25 - 31

Published: Dec. 12, 2024

Pharmacological inhibition of Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) have been firmly established to be an effective approach reduce low-density lipoprotein (LDL) cholesterol levels and cardiovascular events. Subcutaneous administration monoclonal antibodies (evolocumab alirocumab) every 2 or 4 weeks determined a 60 % reduction LDL levels, while the GalNac-siRNA anti PCSK9 (inclisiran) provided lipid lowering activity (-50 %) after initial subcutaneous dose, repeated 3 months followed by maintenance dose 6 months. Although these two approaches potentiality bring majority patients at high very-high risk appropriate targets, their cost represent strong limitation for large-scale use. These problems could overcome development small chemical molecules as oral therapy controlling hypercholesterolemia. In present review, we summarized pharmacological properties that are currently under clinical (DC371739, CVI-LM001, AZD0780), including mimetic peptides enlicitide decanoate (MK-0616) NNC0385-0434.

Language: Английский

Citations

5